Fetal Alcohol Effects on Circadian clocks and POMC

描述(由申请人提供)：胎儿暴露在酒精中会导致胎儿酒精综合征的发展，其特征是胎儿酒精暴露(FAE)后代的各种形态和行为缺陷。这些后代通常表现出临床睡眠觉醒障碍和神经内分泌系统功能异常。最近的研究发现，FAE后代的睡眠-觉醒障碍和神经内分泌功能异常可能与生物钟机制的长期变化有关。利用大鼠动物模型，这项建议确定胎儿接触乙醇是否会导致位于下丘脑弓状核的β-内啡肽神经元的昼夜节律输出长期变化，以及它们对血浆促性腺激素释放的调节。它测试了这样一种假设，即胎儿接触乙醇会导致成人下丘脑交叉上核中央时钟机制的异常表达，从而导致内时钟机制和β-内啡肽神经元的激素输出相改变。它还确定了胎儿接触乙醇是否会改变控制中枢和内部时钟光反应的分子机制。这项拟议的研究使用激光捕获显微镜、免疫组织化学、Western印迹、放射免疫分析和实时RT-PCR技术来识别与中枢和内时钟机制以及β-内啡肽神经元的激素输出相调控密切相关的基因和蛋白表达。拟议的研究应该能更好地理解胎儿接触乙醇对生物钟功能的长期影响。这些信息应该有助于制定治疗策略，以管理睡眠-觉醒障碍和由此产生的FAE后代的健康后果。

DESCRIPTION (provided by applicant): Exposure of a fetus to ethanol can lead to the development of fetal alcohol syndrome, which is characterized by various morphological and behavioral deficits in fetal alcohol-exposed (FAE) offspring. These offspring often show clinical sleep-wake disturbances and abnormalities in the functions of the neuroendocrine system. Recent studies have identified the possibility that the sleep-wake disturbances and neuroendocrine function abnormalities in the FAE offspring are related to long-term changes in circadian clock mechanisms. Employing the rat animal model, this proposal determines whether fetal exposure to ethanol causes long- lasting changes in the circadian output of beta-endorphin neurons located in the arcuate nucleus of the hypothalamus and their regulation of plasma gonadotropin release. It tests the hypothesis that fetal exposure to ethanol causes an abnormality in the adult expression of the central clock mechanisms in the suprachaismatic nucleus of the hypothalamus leading to alteration in the internal clock mechanisms and the phasic hormonal output of beta-endorphin neurons. It also identifies whether fetal exposure to ethanol alters the molecular mechanism governing the photic responses of the central and internal clocks. The proposed research uses laser-captured microscopy, immunohistochemistry, Western blot, radioimmunoassay, and real-time RT-PCR techniques to identify gene and protein expressions that are critically involved in the regulation of central and internal clock mechanisms and the phasic hormonal outputs from beta-endorphin neurons. The proposed studies should provide a better understanding of the long-term consequences of fetal exposure to ethanol in the circadian clock functions. This information should help to develop therapeutic strategies in managing sleep-wake disturbances and the resultant health consequences in FAE offspring.